The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein
The deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein
复制标题
去泛素化酶 OTUD1 通过调节 MCL1 蛋白的稳定性来拮抗 BH3 模拟抑制剂诱导的细胞死亡
DOI：
10.1186/s12935-019-0936-5
复制
发表时间：
2019-08-27
影响因子：
5.8
通讯作者：
Li, Lisheng
中科院分区：
文献类型：
--
作者：
Wu, Lanqin;Lin, Yingying;Li, Lisheng
髓样细胞白血病1（Myeloid cell leukaemia 1，MCL 1）是一种促生存Bcl-2家族蛋白，在细胞生存、增殖、分化和肿瘤发生中起重要作用。MCL 1是一种快速周转蛋白，通过泛素化/蛋白酶体依赖性机制降解。虽然几个E3连接酶已被发现，以促进MCL 1的泛素化，去泛素化酶（DUB），调节其稳定性需要进一步investigation.MethodsThe免疫沉淀被用来确定OTUD 1和MCL 1之间的相互作用。进行泛素化测定以确定OTUD 1对MCL 1的调节。细胞活力用于确定OTUD 1对BH 3模拟抑制剂诱导的细胞死亡的调节。生存分析被用来确定OTUD 1的表达水平和癌症patients.ResultsBy筛选DUB表达文库的生存率之间的关系，我们确定，去泛素化酶OTUD 1调节MCL 1蛋白的稳定性，在酶活性依赖的方式。OTUD 1与MCL 1相互作用并促进其去泛素化。OTUD 1的敲低增加了肿瘤细胞对BH 3模拟抑制剂ABT-263的敏感性，而OTUD 1的过表达增加了肿瘤细胞对ABT-263的耐受性。此外，生物信息学分析数据显示，OTUD 1是肝癌，卵巢癌和特定亚型的乳腺癌和宫颈癌的负预后因子。结论去泛素化酶OTUD 1拮抗BH 3-模拟抑制剂诱导的细胞死亡，通过调节MCL 1蛋白的稳定性。因此，OTUD 1可以被认为是治疗这些癌症的治疗靶点。
BackgroundMyeloid cell leukaemia 1 (MCL1) is a pro-survival Bcl-2 family protein that plays important roles in cell survival, proliferation, differentiation and tumourigenesis. MCL1 is a fast-turnover protein that is degraded via an ubiquitination/proteasome-dependent mechanism. Although several E3 ligases have been discovered to promote the ubiquitination of MCL1, the deubiquitinating enzyme (DUB) that regulates its stability requires further investigation.MethodsThe immunoprecipitation was used to determine the interaction between OTUD1 and MCL1. The ubiquitination assays was performed to determine the regulation of MCL1 by OTUD1. The cell viability was used to determine the regulation of BH3-mimetic inhibitor induced cell death by OTUD1. The survival analysis was used to determine the relationship between OTUD1 expression levels and the survival rate of cancer patients.ResultsBy screening a DUB expression library, we determined that the deubiquitinating enzyme OTUD1 regulates MCL1 protein stability in an enzymatic-activity dependent manner. OTUD1 interacts with MCL1 and promotes its deubiquitination. Knockdown of OTUD1 increases the sensitivity of tumour cells to the BH3-mimetic inhibitor ABT-263, while overexpression of OTUD1 increases tumour cell tolerance of ABT-263. Furthermore, bioinformatics analysis data reveal that OTUD1 is a negative prognostic factor for liver cancer, ovarian cancer and specific subtypes of breast and cervical cancer.ConclusionsThe deubiquitinating enzyme OTUD1 antagonizes BH3-mimetic inhibitor induced cell death through regulating the stability of the MCL1 protein. Thus, OTUD1 could be considered as a therapeutic target for curing these cancers.